title: Phase 0 clinical chemoprevention trial of the Akt inhibitor SR13668.
abstract: SR13668, an orally active Akt pathway inhibitor, has demonstrated cancer chemopreventive potential in preclinical studies. To accelerate the clinical development of this promising agent, we designed and conducted the first-ever phase 0 chemoprevention trial to evaluate and compare the effects of food and formulation on SR13668 bioavailability. Healthy adult volunteers were randomly assigned to receive a single, 38-mg oral dose of SR13668 in one of five different formulations, with or without food. On the basis of existing animal data, SR13668 in a PEG400/Labrasol oral solution was defined as the reference formulation. Blood samples were obtained pre- and post-agent administration for pharmacokinetic analyses. Area under the plasma concentration-time curve (AUC(0-∞)) was defined as the primary endpoint. Data were analyzed and compared using established statistical methods for phase 0 trials with a limited sample size. Participants (n = 20) were rapidly accrued over a 5-month period. Complete pharmacokinetic data were available for 18 randomized participants. AUC(0-∞) values were highest in the fed state (range = 122-439 ng/mL × hours) and were statistically significantly different across formulations (P = 0.007), with Solutol HS15 providing the highest bioavailability. SR13668 time to peak plasma concentration (3 hours; range, 2-6 hours) and half-life were (11.2 ± 3.1 hours) were not formulation-dependent. Using a novel, highly efficient study design, we rapidly identified a lead formulation of SR13668 for further clinical testing. Our findings support application of the phase 0 trial paradigm to accelerate chemoprevention agent development.
authors.affiliation: Mayo Clinic Comprehensive Cancer Center, Rochester, MN, USA.
authors.forename: Joel M
authors.initials: JM
authors.lastname: Reid
authors.forename: Chad A
authors.initials: CA
authors.lastname: Walden
authors.forename: Rui
authors.initials: R
authors.lastname: Qin
authors.forename: Katie L Allen
authors.initials: KL
authors.lastname: Ziegler
authors.forename: John L
authors.initials: JL
authors.lastname: Haslam
authors.forename: Roger A
authors.initials: RA
authors.lastname: Rajewski
authors.forename: Roger
authors.initials: R
authors.lastname: Warndahl
authors.forename: Cindy L
authors.initials: CL
authors.lastname: Fitting
authors.forename: Daniel
authors.initials: D
authors.lastname: Boring
authors.forename: Eva
authors.initials: E
authors.lastname: Szabo
authors.forename: James
authors.initials: J
authors.lastname: Crowell
authors.forename: Marjorie
authors.initials: M
authors.lastname: Perloff
authors.forename: Ling
authors.initials: L
authors.lastname: Jong
authors.forename: Brent A
authors.initials: BA
authors.lastname: Bauer
authors.forename: Sumithra J
authors.initials: SJ
authors.lastname: Mandrekar
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Ames
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Limburg
mesh_terms: D000328:Adult; D016588:Anticarcinogenic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D019540:Area Under Curve; D002227:Carbazoles / Q000494:pharmacology*; D018890:Chemoprevention / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008495:Medical Oncology / Q000379:methods; D008875:Middle Aged; D009369:Neoplasms / Q000378:metabolism / Q000517:prevention & control; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D016588:Anticarcinogenic Agents; D002227:Carbazoles; C523402:SR 13668; D051057:Proto-Oncogene Proteins c-akt